A key step in preparing and selecting pharmaceutically or other biologically useful compounds is identification of structurally-unique lead compounds. In 1990 it was estimated that nearly one-third of the $231 Million average cost for making a new therapeutic compound available for widespread public use was spent in identifying and optimizing a lead chemical structure. Traditionally and currently mass screening of large numbers of compounds and mixtures of compounds has been and is the most successful method for identifying chemical leads. Recent availability of robotic, rapid, high throughput biological screens is beginning to make possible efficient screening of hundreds of thousands of compounds per year.
Most screening libraries consist of a historical collection of compounds synthesized in the course of pharmaceutical research, natural products, and, more recently, peptide libraries. Each of these libraries has limitations. Historical pharmaceutical collections of synthesized compounds contain a limited number of diverse structures which represent only a small fraction of total structural diversity possibilities. Limitations of natural products libraries include the structural complexity of the leads identified and the difficulty of reducing these leads to useful pharmaceutical agents. Peptide libraries are limited to peptides or peptide mimics; to date conversion of peptide chemical leads into pharmaceutically useful, orally active, non-peptide drug candidates in the absence of a small molecule chemical lead has been met with limited success.
Some of the peptide and peptide mimic libraries referred to above were prepared using combinatorial chemistry. A challenge facing medicinal chemists is to translate the success using combinatorial chemistry to prepare peptide and peptide-like compounds into technology suitable for efficiently preparing large libraries of low molecular weight non-peptide compounds. Solid phase chemistry for preparing low molecular weight compounds is desirable to effect such a translation. The following references are examples of the types of solid phase chemistry methods that may be useful in low molecular weight compound combinatorial chemistry.
In 1974, F. Camps et al. (Annales De Quimica 70, 848) reported solid phase synthesis of four related benzodiazepines. More recently Bunin and Ellman (J. Am. Chem. Soc. (1992) 114, 10997, and Proc. Nat. Acad. Sci. USA (1994) 91, 4708) and S. H. DeWitt et al., (Proc. Nat. Acad. Sci. USA (1993) 90, 6909) also reported preparation of a small number of benzodiazepines using solid phase chemistry. Two tetradecene-1-ol acetates also have been prepared on solid supports (C. C. Leznoff et al., Can. J. Chem. (1977) 55, 1143). Additionally, solid phase synthesis of 4,4'-stilbenecarbaldehyde has been reported (J. Y. Wong et al., Angew. Chem. Int. Ed. (1974) 13, 666).
The following references are examples of biphenyl and triphenyl compounds that have been prepared by well known synthetic organic chemical methods. A. A. Patchett et al. recently reported that certain biphenyl acylsulfonamides and biphenyl sulfonylcarbamates are orally active antagonists of the angiotensin II receptor (Medicinal Chemistry Abstract #80 (1993) ACS Meeting-Chicago). Other recently reported angiotensin II antagonists include several imidazopyridine and tetrazole-substituted biphenyl compounds (E. M. Naylor et al., Medicinal Chemistry Abstract #76 (1993) ACS Meeting-Chicago) and a series of carbon-tethered biphenyl pyrrole compounds (J. M. Hamby et al., Medicinal Chemistry Abstract #72 (1993) ACS Meeting-Chicago). Others recently have reported that certain orthobiphenylphenols are leukotriene antagonists (M. J. Sofia et al., Medicinal Chemistry Abstract #5 (1993) ACS Meeting-Chicago).
Preparation of various other substituted biphenyls has been reported. An example of the many references describing methoxy substituted biphenyls is M. G. Banwell et al. which describes certain trimethoxy and tetramethoxy biphenyls that have tubulin binding properties (CA118(19):191308u (1992)). Another such reference describes synthesis of several methoxy and ethoxy-substituted biphenyls for use in a peroxidase indicator system for basic media (CA118(1):3411a (1992)). 2,4',5-Trimethoxy-4-biphenylcarboxylic acid has been reported to have estrogenic activity (CA54:19584c (1959)).
Synthesis of 2,2',5,5'-(tetrapropynl-1-oxy)biphenyl has been reported without indication of its use (CA116(11):105745p (1991)). Similarly, 2,2',6,6'-tetrabenzyloxybiphenyl has been reported (CA110(21):192346b (1988)) and 2,2',3,3'-tetramethoxymethylbiphenyl (CA97(11):91847y (1982)) have been reported without a suggested utility. Preparation of several trisubstituted and tetrasubstituted biphenyls and terphenyls has been reported (CA118(21):212566u (1993)).
Preparation of substituted bisphenyl compounds having a bridging group between the two phenyl rings has been reported. K. Edogawa et al. disclosed substituted bisphenyl compounds having SO.sub.2, S, CMe.sub.2, or O moieties between the rings that are useful in making semipermeable composite membranes for liquid separation (CA109(18):151003y (1986)). Several tetrahydroxy substituted bisphenyl methanes without an indication of their utility have been reported (Marsh et al. Ind. Eng. Chem. (1949) 41, 2176).
Thus there remains a need for methods to efficiently prepare large libraries of low molecular weight non-peptide compounds and to select from such libraries compounds having desired pharmaceutical utility.